An efficient approach to the synthesis of novel spiro

ICC

Original Research Article

Iranian Chemical Communication Payame Noor Universityhttp://icc.journals.pnu.ac.ir

An efficient approach to the synthesis of novel spiro[pyrazoletriazole] and some spiro[pyrazole-phthalazine] derivatives using [BMIm]Cl catalysis Leila Youseftabar-Miri*,a, Hamide Hosseinjani-Pirdehib aDepartment

of Chemistry, Izeh Branch, Islamic Azad University, Izeh, Iran

bDepartment

of Chemistry, TarbiatModares University, P.O. BOX 14115-175 Tehran, Iran

Received: 2 July 2016, Accepted: 31 December 2016, Published: 31 December 2016

Abstract The combination of isatins, active methylene reagents and 4-phenylurazole/ phthalhydrazide in the presence of ionic liquid ([BMIm]Cl) as a solvent catalyst was found to be a suitable and efficient method for the synthesis of the biologically important spirooxindoles. The features of this procedure were characterized by onepot procedure, reasonable reaction times, fairly high yields, and simple isolation procedures. The ionic liquid can be easily separated and reused for several times. Keywords:Ionic Liquid; multi-compound reactions; spirooxindole; isatin; pyrazole. Introduction Modern synthesis design demands high efficiency in terms of minimization of synthetic steps together with maximization of complexity [1]. To meet these goals, chemists have been attempting specially to develop multicomponent reactions (MCRs) [2]. The MCRs strategy offers significant advantages over conventional liner-type synthesis due to its flexible, convergent, and atom efficient nature [2-4]. In this view, designing MCRs without using toxic catalysts in solventfree conditions as well as in recyclable solvents such as ionic liquids is particularly worthwhile for complementing the significant characters of MCRs, so as to satisfy the green chemistry’s principles [5]. Recently, using ionic liquids (ILs) is increasing with a very fast rate because of their beneficial properties

such as undetectable vapor pressure, non-inflammability, wide liquid range, reusability and high thermal stability [6-9]. Moerover, Heterocycles, an important class of organic compounds, constitute more than 70% of promising bioactive and drug molecules presently available in literature [10]. Among these widespread heterocyclic compounds, nitrogen heterocycles occupy a distinct position because of their wide natural abundance and their applications as biologically active pharmaceuticals, agrochemicals, and functional materials are becoming more and more important [11-13]. Among them, the indole ring system is probably the most wellknown heterocycle, a common and important feature of various natural products and medicinal agents [14]. It constitutes the core of spiro-oxindoles,

*Corresponding author: Leila Youseftabar-Miri Tel: +98 (61) 5231068, Fax: +98 (21) 8509739Iran. E-mail:[email protected]

Chem. Commun. … (…) …-…

Leila Youseftabar-Miri, HamideHosseinjani-Pirdehi/ Iranian Chemical Communication … (…) …-…

a recurring subclass of indole alkaloids in nature which exhibits highly pronounced biological activities, thus deserving to occupy a unique place among pharmacological agents [15]. Similarly, heterocycles containing the pyrazole, phthalazine and urazole moieties played a crucial role in the history of heterocyclic chemistry and have been used as important pharmacores and synthons in the field of organic chemistry and drug designing [16]. In particular, they are used as antibacterial, antifungal, antiviral, antiphrastic and insecticidal agents [17-23]. Upon these salient aspects, incorporation of the two pharmacophoric, pyrazole and oxindole, motiffing into a single molecule via efficient and environmentally benign synthetic methods would be beneficial [24]. Encouraged by these observation and in continuation of our earlier studies on the synthesis of spirooxindole heterocyclic compounds and the use of ionic liquid as catalyst in organic synthesis,[30-33] we report, herein, the synthesis of novel spiro[pyrazole-triazole] and known derivatives of spiro[pyrazolephthalazine] under catalysis of the ionic liquid. Experimental Matreials and methodes All chemicals were purchased from Merck or Fluka Chemical Companies. All known compounds were identified by comparison of their melting points and spectral data with those reported in the literature. Progress of the reactions was monitored by thin layer chromatography (TLC) using silica gel SIL G/UV 254 plates. IR spectra were recorded using a Shimadzu IR- 470 spectrometer with KBr plates. 1H NMR and 13C NMR spectra were recorded on

a Bruker Avance-400 MHz spectrometer. General procedure A mixture of isatindeivatives1a-e (1 mmol) malononitrile/ ethyl cyanoacetate 2a-b (1 mmol) and 4phenylurazole/ phthalhydrazide3a-b (1 mmol) was added to a vial containing a magnetic stirring bar and (1 mL) of the ionic liquid [BMIm]Cl. The reaction mixture was sealed and stirred at 90 °C until until the starting materials disappeared (Table 1). At this stage, the products due to poor solubility in the ionic liquid appeared as a precipitate. In order to extract the ionic liquid, after completion of the reaction, the residue was washed with (2 × 10 mL) water. Washing the solid residue with ethanol (10 mL, 95.5%) has given remarkably pure powders of product 4a-k. The ionic liquid was recovered from the aqueous extracts by evaporating water under reduced pressure and reused in the next cycles (Scheme 4). The selected spectral data 7-Amino-6-carbonitrile-1,2,3,5,2',3'hexahydro-1,3,2'-trioxo-2-phenyl spiro[pyrazolo[1,2 a][1,2,4]triazolo5,3'-indole (4a). Red solid (0.33 g, 90%), IR (KBr): ν= 3438, 3330, 1748, 1702, 1662, 1527, 1650 cm-1. 1HNMR (400 MHz, DMSO): δ= 6.91 (1H, d, J= 8.0 Hz), 7.06 (1H, t, J= 7.6 Hz), 7.36-7.41 (1H, m), 7.44-7.49 (5H, m), 7.51 (2H, s, NH2), 7.56-7.60 (1H, m), 10.96 (1H, s, NH) ppm.13C NMR (100 MHz, DMSO): δ= 59.3, 71.5, 112.7, 118.3, 123.2, 125.2, 126.5 (2C), 128.1, 129.3 (2C), 132.4, 138.8, 151.2, 153.9, 159.8, 184.9 ppm. Anal. Calcd. for C19H12N6O3; C 61.29 , H 3.25 , N 22.57 ; found C 61.10 , H 3.12 , N 22.19. 7-Amino-5'-boromo -6-carbonitrile1,2,3,5,2',3'-hexahydro-1,3,2'-trioxo-

An efficient approach to the synthesis of novel spiro[pyrazole-triazole] and…

2-phenyl-spiro[pyrazolo[1,2a][1,2,4]triazolo-5,3'-indole (4b) Yellow solid(0.37 g, 84%), IR (KBr): ν= 3357, 3248, 3193, 2206, 1763, 1705, 1659 cm-1. 1HNMR (400 MHz, DMSO): δ= 6.90 (1H, d, J=8.4Hz), 7.49 (1H, d.d.d, J=2.0 HZ, 1.6 Hz, 6.4Hz), 7.83 (1H, d, J=1.6Hz), 8.0-8.03 (3H, m), 8.04-8.08 (2H, m), 8.30-8.32 (1H, m), 8.40 (2H, s, NH2), 11.10 (1H, s, NH) ppm. 13C NMR (100 MHz, DMSO): δ= 59.9, 69.9, 112.7, 114.7, 127.5, 128.0, 128.1, 128.2, 128.3, 129.3, 134.9, 135.5, 141.9, 152.4, 152.9, 156.8, 172.6 ppm. Anal. Calcd. for C19H11BrN6O3; C 50.57, H 2.46 , N 18.62 ; found C 50.18 , H 2.32 , N 18.51. Ethyle-7-amino -6-carbonitrile1,2,3,5,2',3'-hexahydro-1,3,2'-trioxo2-phenyl-spiro[pyrazolo[1,2a][1,2,4]triazolo-5,3'-indole]-6carboxylate (4c) White solid (0.38 g, 91%), IR (KBr): ν= 3470, 3350, 2983, 1784, 1724, 1622 cm-1. 1HNMR (400 MHz, DMSO): δ= 0.86 (3H, t, J= 6.8Hz), 3.84 (2H, q, J= 6.4 Hz), 6.85 (1H, d, J= 7.6 Hz), 7.00 (1H, t, J= 7.2 Hz), 7.27 (1H, t, J= 7.6 Hz), 7.40-7.43 (4H, m), 7.53 (2H, d, J= 7.6 Hz), 7.55 (2H, s, NH2), 10.76 (1H, s, NH) ppm. 13C NMR (100 MHz, DMSO): δ= 14.2 (CH3), 59.1 (CH2), 71.2, 83.0, 110.4, 122.6, 125.1, 127.1 (2C), 127.6, 129.5, 129.7 (3C), 130.5, 130.9, 143.3, 149.2, 151.1, 163.6, 173.9 ppm. Anal. Calcd. for C21H17N5O5; C 60.14 , H 4.09 , N 16.70; found C 60.01 , H 4.11 , N 16.23. Ethyle-7-amino-5'-chloro -6carbonitrile-1,2,3,5,2',3'-hexahydro1,3,2'-trioxo-2-phenylspiro[pyrazolo[1,2-a][1,2,4]triazolo5,3'-indole]-6-carboxylate (4d) White solid (0.41 g, 90%), IR (KBr): ν= 3476, 3364, 1788, 1752, 1727, 1681.cm-1. 1HNMR (400 MHz, DMSO): δ= 0.89 (3H, t, J=7.6Hz), 3.87

(2H, q, J= 6.8 Hz), 6.86 (1H, d, J= 8.0 Hz), 7.32 (1H, d, J= 8.0 Hz), 7.43-7.48 (3H, m), 7.53 (2H, d, J= 7.6 Hz), 7.57 (2H, s, NH2), 7.69 (1H, s), 10.88 (1H, s, NH) ppm. 13C NMR (100 MHz, DMSO): δ= 14.3 (CH3), 59.2 (CH2), 71.3, 83.2, 111.8, 125.7, 126.6, 127.1 (2C), 129.2, 129.4, 129.7 (3C), 130.4, 131.0, 142.2, 149.0, 150.5, 163.5, 173.9 ppm. Anal. Calcd. for C21H16ClN5O5; C 55.58 , H 3.55 , N 15.43; found C 55.51 , H 3.49 , N 15.25. 3'-Amino-2,5',10'-trioxo-5',10'dihydrospiro[indoline-3,1'pyrazolo[1,2-b]phthalazine]-2'carbonitrile (4e) Yellow solid (0.32g, 90%), IR (KBr): ν= 3349, 3301, 3248, 2212, 1754, 1704, 1600 cm-1.1H NMR (DMSO-d6): δ=93(1H, d, J= 8.0 Hz), 7.01(1H, t, J= 7.6 Hz), 7.31(1H, t, J= 7.6 Hz), 7.48 (1H, d, J= 7.6 Hz), 7.98-8.02 (2H, m), 8.03-8.07(1H, m), 8.36 (2H, s, NH2), 10.96 (1H, s, NH). 3'-Amino-5-methyl-2,5',10'-trioxo5',10'-dihydrospiro[indoline-3,1'pyrazolo[1,2-b]phthalazine]-2'carbonitrile (4f) Yellow solid (0.33 g, 88%), IR (KBr): ν= 3378, 3300, 3026, 2201, 1726, 1710, 1660 cm-1. 1H NMR (DMSO-d6): δ= 3.67 (3H, s, CH3), 6.84(1H, d, J= 8.4 Hz), 6.86(1H, d.d, J= 2.4 Hz, J= 2.4 Hz ), 7.22(1H, d, J= 2.4 Hz), 7.99-8.04 (2H, m), 8.06-8.08(1H, m), 8.35 (2H, s, NH2), 10.76 (1H, s, NH). 3'-Amino-5-bromo-2,5',10'-trioxo5',10'-dihydrospiro[indoline-3,1'pyrazolo[1,2-b]phthalazine]-2'carbonitrile (4g) Yellow solid (0.37 g, 86%), IR (KBr): ν= 3356, 3248, 3022, 2206, 1763, 1705, 1659 cm-1.1H NMR (DMSO-d6): δ=0.90(1H, d, J= 8.4 Hz), 7.49(1H, d.d, J= 2.0 Hz, J= 2.0 Hz ), 7.83(1H, d, J= 1.6 Hz), 8.00-8.03 (2H, m), 8.058.08(1H, m), 8.39 (2H, s, NH2), 11.09 (1H, s, NH).


8.32(1H, m), 10.75 (1H, s, NH), 11.55 (2H, s, NH2). Results and discussion With this background in mind and in line with our interest in the synthesis of spiro compounds,[30-35] we report an efficient and environmentally benign protocol for the synthesis of pyrazole motifs compounds by condensation of isatin derivatives 1a-e, malononitrile/ ethyl cyano-acetate 2a-b and 4phenylurazole/ phthalhydrazide3a-b catalyzed by ionic liquid [BMIm]Cl and without using any solvent or additional catalyst. The products were obtained in high yields by a simple work-up (Scheme 1). At the onset of the study, an equimolar mixture of the model substrates; isatin 1a, malononitrile 2a, and 4- phenylurazole 3a was treated with the selected ionic liquids without any added catalyst and solvent (Scheme 2).

3'-Amino-5-chloro-2,5',10'-trioxo5',10'-dihydrospiro[indoline-3,1'pyrazolo[1,2-b]phthalazine]-2'carbonitrile (4h) Yellow solid (0.35g, 90%), IR (KBr): ν= 3354, 3247, 3192, 2207, 1763, 1704, 1658 cm-1.1H NMR (DMSO-d6): δ=.95(1H, d, J= 8.4 Hz), 7.36(1H, d.d, J= 2.4 Hz, J= 2.4 Hz), 7.71(1H, d, J= 2.0 Hz), 8.00-8.03 (2H, m), 8.068.08(1H, m), 8.39 (2H, s, NH2), 11.08 (1H, s, NH). Ethyl 3'-amino-5-bromo-2,5',10'trioxo-5',10'-dihydrospiro[indoline3,1'-pyrazolo[1,2-b]phthalazine]-2'carboxylate(4i) Yellow solid (0.36 g, 89%), IR (KBr): ν= 3435, 3324, 2892, 1733, 1715, 1672 cm-1.1H NMR (DMSO-d6): δ= 0.88(3h, t, J= 6.8 Hz), 3.86 (2H, q, J= 7.2 Hz), 6.93(1H, d, J= 8.0 Hz), 7.30(1H, d, J= 7.6 Hz), 7.87-7.91(2H, m), 7.99-8.03 (2H, m), 8.05-8.07(1H, m), 8.80-

H2N O R1

O

CN O + N H (1a-e)

NH NH

+ R2

[BMIm]Cl

R2

R1

90 oC

N H

O (3a-b)

(2a-b)

O N N

N Ph OO

R1 or

N H

O

O

O

NH NH

NH = Ph N NH NH NH O O (3a)

R2= (2a=CN, 2b=CO2Et)

O (3b)

Scheme 1. Reaction protocol for the synthesis of spirooxindoles compounds

CN O N H 1a

H2N

O

O CN

HN HN

Ph O

2a

3a

O N N

NC N H 4a

Scheme 2. The model reaction

N Ph OO

N N

R2

(4a-k)

R1=(1a= H, 1b=Br, 1c=Cl, 1d=NO2, 1e=CH3)

O

H2N

OO


The results are shown in Table 1, a short range of pH conditions associated with the selected ionic liquids to investigate the effect of acidity or basicity of these media on the reaction performance. As can be seen (Table 1), the condensation was performed in different ionic liquids, but the efficiency and the yield of the reaction in weak basic ionic liquid [BMIm]Cl were higher than in other ionic liquids, thereby making [BMIm]Cl the most suitable reaction medium for successive reactions (Table 1). The results show that Brønsted acid-base ionic liquids such as TMGT and TMGTf lead to the products in low yields and the reaction time is longer than neutral ionic liquid [BMIm]BF4. The acidic ionic liquid, [BMIm]HSO4, was not as effective As effective as [BMIm]Cl. The result showed that different ILs exhibit a dramatic difference in the yield of 4a, attributed to the tunable physical properties of ionic liquids. In order to show the merit of the catalyst, we have

compared the obtained results in the synthesis spiro[pyrazole-phthalazine] catalyzed by [BMIm]Cl, with some hetrogeneous and homogeneous catalysts, as reported in the literature (Table 2). The harsh reaction conditions, longer reaction times and irresability of other methods make our system a better choice [25-29]. After detecting [BMIm]Cl as the more efficient catalyst solvent, we examined the method with a range of substrates to determine the reaction specificity and scope. Consequently, various substituted isatins (1a-e) were used to react with malononitrile (2a) or ethyl cyano-acetate (2b) and 4-phenylurazole (3a) phthalhydrazide (3b) was treated with the selected ionicliquid under the optimized conditions (Table 1). These results are compiled in Table 2. As shown in Table 3, in all cases, the reaction gives the products good yields and prevents problems associated with solvent usage such as cost, handling, safety and pollution.

Table 1. Optimization of reaction conditions Entry

Catalysta

Conditions

Time(min)

Yield(%)b

1

---

Solvent-free (90°C)

180

---

2

p-TSA

EtOH (reflux)

180

---

3

FeCl3

EtOH (reflux)

180

---

4

ZnCl2

EtOH (reflux)

180

---

5

DABCO

EtOH (reflux)

180

Trace

6

[BMIm]Cl


180

Intermediate 5

7

[BMIm]Cl


40

90

8

[BMIm]BF4


300

21


9

[BMIm]HSO4


240

---

10

TMGT


300

10

11

TMGTf


240

10

12

[BMIm]LiCl


240

18

13

[BMIm]Cl

EtOH (Reflux)

90

48

a

Reaction conditions: isatin (1 mmol), malononitrile (1 mmol), 4-phenylurazole (1mmol) and catalyst (1 mmol) or ionic liquid (1 ml). bIsolated yields.

Table 2. Comparision of [BMIm]Cl with other catalysts for the synthesis of 3'-Amino2,5',10'-trioxo-5',10'-dihydrospiro[indoline-3,1'-pyrazolo[1,2-b]phthalazine]-2'-carbonitrile Entry

Catalyst and Conditions

Reaction time

Yield(%)

Ref.

(min) 1

CH3CN/Piperidine//reflux

240

80

[28]

2

EtOH/L-Proline/reflux

120

90

[29]

3

[DBU][AcOH]/100°C

60

90

[26]

4

PEG-600/NiCl2/100°C

60

90

[25]

5

EtOH/Piperidine/Sonication/r.t

30

90

[27]

6

EtOH/Piperidine/reflux

240

78

[27]

7

[BMIm]Cl/Neat/90°C

40

90

This work

A plausible mechanism for the formation of the selected product 4a-k in the presence of [BMIm]Cl ionic liquid as a catalyst solvent is outlined in (Scheme 3). The condensation of isatin 1a-e, malononitrile/ ethyl cyano-acetate 2a-b and compound3a-b may occur by a mechanism of Knoevenagel condensation, Michael addition, intramolecular cyclization, and isomerization. Initially, intermediate 5

is formed by Knoevenagel condensation of isatin 1a-e and malononitrile/ ethyl cyano-acetate 2a-b by the action of ionic liquid.Then, the proton of compound 3a-b is attacked by intermediate 5 to form intermediate 6. Michael addition of intermediate 6 on 5 leads to the formation of 7, followed by cyclization and isomerization, affording the corresponding products 4a-k (Scheme 3).


+ R H Cl

Me N

O

HN O NC

Me N Me N N

R

R

R

C

O

Cl-

O

R H CN

N H 1a-e

2a-b

Bu

N O HN HN

O NH

R

N

Bu

O

N H

H+ ClMe N

R

O

NC R

N

Bu

Bu

H+ Cl-H2O

N

3a-b O

5

O R

N C

HN

HN N

R

O O

R R

N H 6

H

H2N

O N N

O N O H 7

R R

O N N

N O H 4a-k

O

Scheme 3. Possible mechanism for synthesis of spirooxindole systems 4a-k in the presence of [BMIm]Cl as a catalyst

The structures of the new compounds 4a-d were confirmed by IR, 1 H, 13C NMR and CHN as well as mass spectral data. For example, the IR spectrum of 4a showed distinct absorptions at 3435, 3324, and 1733, 1672 cm-1 corresponding to vibrations of its NH and CO groups. A relatively wide range of chemical shifts, δ 6.857.60 ppm, was observed for the

aromatic protons of this product, and the presence of two broad singlets at 10.96 and 7.51 ppm with a 1:2 ratios was detected, attributed to NH and NH2, respectively. The 13C NMR spectrum of 4a showed 19 distinct resonances in agreement with the proposed structure. The characteristic signal due to the spiro carbon displayed at δ 59.3.


Table 3. Synthesis of spirooxindoles derivatives 4a-k in the presence of [BMIm]Cl Entry

Compound

Compound

Compound

1

2

3

Prouduct

H2N

O N N Ph N OO

NC 1

1a

2a

3a

N H

(4a)

H2N

2

1b

2a

3a

Br

O N N Ph N OO

NC

(4b)

N H

H2N 1a

2b

3a

(4c)

N H

N N Ph N OO

H2N 4

1c

2b

3a

EtO2C Cl (4d)

N H

5

1a

2a

O N N Ph N OO

N N

3b

1e

2a

3b

N N

NC

(4f)

7

1b

2a

3b

(Lit)b

40

90

40

88

290-292(---)

45

91

286-288(---)

45

90

284-286(---)

40

90

35

88

35

86

N OO H

NC

(4g)

282-284(---)

268-270(272274)[25-29]

280-282(278279)[25,27]

O

H2N Br

(%)a

O

H2N 6

(min)

N OO H

(4e)

H3C

M.p. (oC)

O

H2 N NC

yield

O

EtO2C 3

Time

N N O N O H

›350(›350)[2529]

An efficient approach to the synthesis of novel spiro[pyrazole-triazole] spiro[pyrazole triazole] and… and

O

H2N 8

1c

2a

Cl

3b

N N

NC

(4h)

9

1a

2b

1b

2b

3b

N N

EtO2C

(4j)

1c

2b

3b

Cl

87

40

90

O N O H

EtO2C

(4k)

285-287(281283)[25-29]

331-333(328330)[25-29]

O

H2N 11

40

334)[25,27]

O

H2N 10

89

N OO H

(4i)

Br

40

325-327(332-

O N N

3b

90

N OO H

H2 N EtO2C

35

N N N OO H

332-334(330332)[25-27]

a

Isolated yields, b Ref.[25-29]

In the next phase of the study, the viability of catalysis in the recycled ionic liquid in model reaction was evaluated. After completion of the reaction, the ionic liquid was washed using water, evaporated under reduced

pressure and then subjected to the next run with the same substrates and the same reaction time. Scheme 4 displays similar high conversions obtained after consecutive recycling of the ionic liquid (Scheme 4).

Scheme 4. Recyclability of [BMIm]Cl


Conclusion In summary, an efficient method for synthesis of spiro-annulated pyrazoleoxindole ring system by using simple and readily available starting materials under catalysis of the ionic liquid, [BMIm]Cl, was introduced here. The ionic liquid plays the role of catalyst solvent and can be recovered to be reused several times. Another advantage of the present method is that it requirs no metal catalysts or additional solvent proceeding with appropriate rate with respect to the methods that gave similar skeletone. This method not only affords the products in excellent yield but also avoids the problems associated with catalyst cost and pollution. We expect this method to find extensive applications in the field of combinatorial chemistry, diversityoriented synthesis, and drug discovery. Acknowledgments We gratefully acknowledge the financial support from the Research Council of University of Islamic Azad University, Izeh Branch. References [1] B.M. Trost, Science, 1991, 254, 1471-1477. [2] H. Bienayme, C. Hulme, G. Oddon, P. Schmidt, Chem. Eur. J., 2000, 6, 3321-3329. [3] R.V.A. Orru, M. De Greef, Synthesis, 2003, 1471-1499. [4] A.J. von Wangelin, H. Neumann, D. GÖrdes, S. Klaus, D. Strubing, M. Beller, Chem. Eur.J., 2003, 9, 42864294. [5] (a) M.A.P. Martins, C.P. Frizzo, D.N. Moreira, N. Zanatta, H. Bonacorso, Chem Rev., 2008, 108, 2015-2050. (b) J.D. Holbrey, M.B. Turner, W.M. Reichert, R.D. Rogers, Green Chem., 2003, 5, 731-736. [6] M. Fremantle, Chem. Eng. News, 1998, 76, 32-37.

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